Bursting Neurons and Fading Memories: An Alternative Hypothesis of the Pathogenesis of Alzheimer's Disease

148 Pages·2014·17.83 MB·English

by  Michael R. D'Andrea

Bursting Neurons and Fading Memories
An Alternative Hypothesis of the Pathogenesis
of Alzheimer’s Disease
Michael R. D’Andrea
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DEDICATION
I dedicate this book to:
• Those who passed away from this dreadful disease and those who
caringly donated their loved ones’ tissues to research. I would not
have discovered so much without their ultimate contributions.
Those who have AD and their family’s caregivers, for help is soon
on the way.
• My wife Patty, my oldest daughter Dr. Michelle and her husband,
Kevin, my son Michael, and my youngest daughter, Stephanie, all
of whom have given me endless support and love.
• My parents, Henry and Angela, for all their eternal love and
support, and especially for buying my first microscope as a
Christmas gift when I was 7 years old, setting my scientific career
in motion.
ABOUT THE AUTHOR
Michael R. D’Andrea received his PhD in cell and developmental biol-
ogy, his MS in molecular biology at Rutgers University, New Brunswick,
NJ, and his BA in psychobiology at Western Maryland College, West-
minster, MD. His dissertation work utilized molecular and histological
assays to study the regulation of DNA topoisomerases in human cancers.
His earlier career concerned the use of the high-magnification electron
microscope to support oncogenesis in preclinical models, and then
moved into a new field where he and his peers coinvented the chorionic
villus sampling method for clinical chromosomal analysis at Thomas
Jefferson Medical School. In the late 1980s and early 1990s, he mastered
immunohistochemical methods at the light and electron microscopy
levels when he began publishing his work in scientific journals. However,
it wasn’t until the mid-1990s, while working at Johnson & Johnson’s
Pharmaceutical Research & Development as the Target Validation Team
Leader, that he became engaged in Alzheimer’s disease (AD) research.
The team that he established was responsible for supporting target
discovery and validation, while supporting biomarker discovery in
preclinical and experimental models using genomic, proteomic, and
histopathological methods across many therapeutic areas. For this work,
he was honored with over a dozen Leadership and Scientific awards.
Currently, he has over 100 peer-reviewed scientific publications and
invited reviews, about one-third of which concern the neuropathology of
AD, and holds 11 scientific patents. He has reviewed hundreds of papers
and served on several editorial boards for many scientific journals, has
reviewed international grants in the AD field, and is currently on the editorial
board of the journal Biotechnic & Histochemistry. He has been invited to
speak at numerous international, national, and regional meetings, as well
as at universities and other companies to discuss his novel observations
concerning the origin of amyloid plaques, the existence of various plaque
types, and most recently the assertion that AD is also an autoimmune disease,
all of which are presented in this book. Most recently, Michael established a
contract research company, Slidomics, LLC (www.slidomics.com), to apply
his histopathological and target validation expertise by providing high-
quality data and analysis much like what you see in this book.
PREFACE
So how do you write a book about Alzheimer’s disease (AD)? You can
state the facts, or analyze the progress the field has made so far, or dis-
cuss your personal experiences. But how do you write a book about a
possible cure for AD? Quickly, I suppose. The sooner progress can be
made, the better.
When I first had the idea for this book, I was shocked that it took
so long for the thought to come to me. By that time I had given up on
having any impact in Alzheimer’s research, despite my over 30 publica-
tions, many presentations, and 16 years in the field. Since my research
has contradicted the mainstream hypotheses in the field, hopefully
those of you who do know what that is like can sympathize with
my distress and frustration at the current state of affairs. But to
finally write a summary of these findings in one cohesive book now
seems obvious, and writing it came so naturally that I only wish I
embarked on this journey sooner, if only because it will never be too
soon to find a cure for AD.
While I have very high hopes for how this book might change the
direction of AD research, at the very least it has already been a huge per-
sonal relief to write, if only to say “look back over here, I think I’ve got
it.” It’s a bit dramatic perhaps to call this my “swan song,” but I think of
it more as passing on the torch, hopefully to a generation of bright, pas-
sionate, unbiased, but skeptical scientists who can continue my legacy of
research. The feeling that years of personal emotional investment into
this field might still be valuable is my relief.
And if you’re in the field, you must know that now, more than ever,
there is an imperative need to consider alternative hypotheses about
the causes of AD. The field needs controversy to move forward and
I certainly supplied my fair share since the late 1990s. If I wasn’t
completely confident in these personal findings and the direction of
my hypothesis, I’d remain quiet and frustrated as you may be with
the failed “all-eggs-in-one-basket” approach that has stifled creative
thinking in the field to explain neuronal death leading to a cure. I hope
xiv Preface
reading about this hypothesis not only exposes the flaws in the cur-
rent line of research but also convinces you exactly where to go next.
And if you don’t believe what I’ve found, please conduct research to
support or contradict me! Again, this field needs new ideas, no matter
where they come from or what they are, and now that the oppressive
cloud of the reigning hypothesis is dissipating, it is time to consider
alternative hypotheses.
Writing this book and recalling the story of my many contribu-
tions to the field has been an emotional experience. I have relived the
pride in designing one set of assays after the next, the excitement of
reading the hundreds of microscopic slides of human tissues, and the
frustration of the political challenges I faced by publishing controver-
sial data. As you will discover, I never had a passion to cure AD when
the story began, nor did I have any stakes in the field as a cell biolo-
gist. I was merely the lucky scientist who came across the provocative
results I present here. I regret that I could not make a stronger impact
previously through each of my publications and presentations, but
I hope I can now by collating this work into one coherent and logi-
cal story. I encourage you to read with a critical mind, dig up these
detailed publications, question everything you know or have learned
about AD, and consider what must happen for the field to move for-
ward and what you can do to help. Although I have addressed the
many editorial comments of the reviewers and audience members I
have faced, as you will read, I will depend on you to assess the scien-
tific value of my work on its own merits, in the context of the current
state of the AD field.
Lastly, thank you for sharing in my journey. It is not easy being the
odd one out, and here more than ever I am putting myself up for criti-
cism and disdain. Please know that everything I present is for the better-
ment of the field, for our futures, and hopefully serves to move us more
quickly toward a cure for this tragic, draining, and terrifying condition
known as AD.
Conformity may give you a quiet life; it may even bring you to a University
Chair. But all change in history, all advancement, comes from the noncon-
formists. If there had been no trouble-makers, no Dissenters, we should still be
living in caves.
AJP Taylor
Preface xv
Disclosure statement: Although all of the data presented in this book
have been published in peer-reviewed scientific journals, I make no claims
on how to treat AD patients beyond what is already known in the literature.
The sole intention of this book is to present novel hypotheses for consid-
eration in light of the failed clinical studies based on the classical amyloid
cascade hypothesis. As with any scientific trials, if the hypothesis is proven
false, then other hypotheses should be considered for testing.
ACKNOWLEDGMENTS
Especially to my immediate family for providing direction, style, and
edits for the book.
Dr. Bruce Damiano, Dr. Charlie Saller, and Peter Cronk, Esq., for
I am also indebted to them for their keen edits, constructive criticisms,
and support to move ahead with this project.
To all of my past collaborators, hopefully they know who they are
and appreciate the contributions they have made to my line of research
and the AD field.
To the Elsevier publishing staff, especially Dr. Natalie Farra for her
supportive contributions to this book.
Thank You!
INTRODUCTION
… dead ends in Alzheimer’s research …
How has Alzheimer’s disease (AD) affected your life? Is it in your pro-
fession to directly care for or treat AD patients? Are you in the scientific
and medical community trying to discover the cause? Do you have a
loved one who is currently suffering from this terrible disease? Or, per-
haps, you have a sideline curiosity or simple fascination with AD. Even
if AD does not impact your life today, the odds are sadly staggering that
it will someday.
AD diagnoses are increasing at an alarming rate: today, as many
as half of people over 80 will be afflicted.1 AD is officially the sixth
leading cause of death in the United States and fifth leading cause
of death for those of ages 65 and older; that is more than prostate
cancer and breast cancer combined.2 In other words, the odds are high
that your parents, siblings, other relatives, and/or neighbors will be
diagnosed with AD as they age. To have a loved one not only forget
you but also require f ull-time care over the course of several, perhaps
many years can cripple any human spirit, as some of you undoubtedly
and unfortunately already know.
It is impossible to overstate the urgency and dire state of AD today,
and there are no signs of slowing down. Deaths from AD increased 68%
between 2000 and 2010, and AD is among the top 10 causes of death in
America that cannot be prevented, cured, or even slowed.2 About 13.8
million Americans will be living with AD by 2050, up from 4.7 million in
2010, and according to the World Health Organization, about 35.6
million people around the world have dementia, with 7.7 million new cases
each year.3 Imagine that every 67 seconds, someone develops AD.2 This
disease not only negatively impacts the immediate family and friends of
the victim but also is one of the most costly modern medical conditions
to support. In 2014, the direct costs to American society for AD care
will total an estimated $214 billion, and if there is no breakthrough cure
or way to prevent or even slow down the progression of AD, the costs
may reach up to a staggering $1.2 trillion by the year 2050.2
xx Introduction
If there is still no cure for or better understanding of AD today, it’s
not for lack of trying. In the United States alone, government initia-
tives have funded $2.5 billion in AD research just over the past 4 years
including a projected $566 million in 2015.4 Despite these impressive
numbers, researchers dedicated to the field have had few breakthroughs.
Most recently, a series of high-profile, expensive clinical trials hedg-
ing their bets on one hypothesis have all failed, leading to a dead-end
in the field. These recent failures have fueled a mounting frustration
and a lack of confidence in the current direction of the study of AD.
In the face of a stagnant field, with all prominent and heavily f unded
current initiatives in the field being uncompromising failures, this book
is intended to be the impetus for change, for a new approach, and
for hope to combat this terrible condition. With this book, I hope to
change your perception of the causes of AD, and that you will come to
understand how I developed this novel hypothesis, which will logically
explain why research has reached a dead-end while presenting a road
map for alternative approaches.
All of the evidence supporting this hypothesis concerning the causes
of AD is presented in a general chronological order (not a scientific or
“textbook” order) with actual events. Each study is accompanied with
rationale, commentary, technical and observational details, and inter-
pretations of these experiments. The spirit of the book is not a data
download filled with hundreds of references, but a story of my journey
of how I was forced to confront peers in a very political field with data
contradicting their long and dearly held beliefs. Again, this is a story, not
a journal article, and I do not mean for this book to be the end-all AD
reference book. Although there are many more thorough sources on the
history of AD than I can possibly cover in this book, I can summarize
some of the important aspects of AD to help tell my tale.
I sincerely hope that as you read this book, it gives you a new per-
spective on the causes of neuronal death leading to AD, and that
if you are in the field, it stimulates you to pursue and test some of
these findings to help cure this disease. I hope that you find my stories
invigorating, informative, provocative, and yet frustrating in the face of
a politically charged academic system primarily based on old science.
I encourage you to approach this book with an open mind and little
bias, and only ask that you refrain from enacting your commentary